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==Crystal structure of a de novo-designed mini-protein targeting FGFR== | ==Crystal structure of a de novo-designed mini-protein targeting FGFR== | ||
<StructureSection load='7n1k' size='340' side='right'caption='[[7n1k]]' scene=''> | <StructureSection load='7n1k' size='340' side='right'caption='[[7n1k]], [[Resolution|resolution]] 3.01Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N1K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N1K FirstGlance]. <br> | <table><tr><td colspan='2'>[[7n1k]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N1K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N1K FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7n1k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n1k OCA], [https://pdbe.org/7n1k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n1k RCSB], [https://www.ebi.ac.uk/pdbsum/7n1k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n1k ProSAT]</span></td></tr> | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7n1j|7n1j]]</div></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7n1k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n1k OCA], [https://pdbe.org/7n1k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n1k RCSB], [https://www.ebi.ac.uk/pdbsum/7n1k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n1k ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains an outstanding challenge(1-5). We describe a general solution to this problem which starts with a broad exploration of the very large space of possible binding modes to a selected region of a protein surface, and then intensifies the search in the vicinity of the most promising binding modes. We demonstrate its very broad applicability by de novo design of binding proteins to 12 diverse protein targets with very different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and following experimental optimization bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of five of the binder-target complexes, and all five are very close to the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvement of both. Our approach now enables targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications. | |||
Design of protein binding proteins from target structure alone.,Cao L, Coventry B, Goreshnik I, Huang B, Park JS, Jude KM, Markovic I, Kadam RU, Verschueren KHG, Verstraete K, Walsh STR, Bennett N, Phal A, Yang A, Kozodoy L, DeWitt M, Picton L, Miller L, Strauch EM, DeBouver ND, Pires A, Bera AK, Halabiya S, Hammerson B, Yang W, Bernard S, Stewart L, Wilson IA, Ruohola-Baker H, Schlessinger J, Lee S, Savvides SN, Garcia KC, Baker D Nature. 2022 Mar 24. pii: 10.1038/s41586-022-04654-9. doi:, 10.1038/s41586-022-04654-9. PMID:35332283<ref>PMID:35332283</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7n1k" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Lee S]] | [[Category: Lee, S]] | ||
[[Category: Park | [[Category: Park, J S]] | ||
[[Category: Binder]] | |||
[[Category: De novo protein]] | |||
Revision as of 13:22, 18 May 2022
Crystal structure of a de novo-designed mini-protein targeting FGFRCrystal structure of a de novo-designed mini-protein targeting FGFR
Structural highlights
Publication Abstract from PubMedThe design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains an outstanding challenge(1-5). We describe a general solution to this problem which starts with a broad exploration of the very large space of possible binding modes to a selected region of a protein surface, and then intensifies the search in the vicinity of the most promising binding modes. We demonstrate its very broad applicability by de novo design of binding proteins to 12 diverse protein targets with very different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and following experimental optimization bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of five of the binder-target complexes, and all five are very close to the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvement of both. Our approach now enables targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications. Design of protein binding proteins from target structure alone.,Cao L, Coventry B, Goreshnik I, Huang B, Park JS, Jude KM, Markovic I, Kadam RU, Verschueren KHG, Verstraete K, Walsh STR, Bennett N, Phal A, Yang A, Kozodoy L, DeWitt M, Picton L, Miller L, Strauch EM, DeBouver ND, Pires A, Bera AK, Halabiya S, Hammerson B, Yang W, Bernard S, Stewart L, Wilson IA, Ruohola-Baker H, Schlessinger J, Lee S, Savvides SN, Garcia KC, Baker D Nature. 2022 Mar 24. pii: 10.1038/s41586-022-04654-9. doi:, 10.1038/s41586-022-04654-9. PMID:35332283[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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